Patients with bipolar disorder suffer recurrent, alternating cycles of mania and depression. A number of anecdotal reports have suggested that lecithin (phosphotidylcholine), a dietary precursor of choline, has anti-manic properties that might be useful in treating patients with this disorder (Cohen et al., Am. J. Psychiatry 137:242-243 (1980); Schreier, Am. J. Psychiatry 139:108-110 (1982); Leiva, Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 14:423-429 (1990)). In addition, a controlled clinical study performed more than a decade ago reported that lecithin has a modest anti-manic effects when given to patients with bipolar illness (Cohen et al., Am. J. Psychiatry 139:1162-1164 (1982)).
At the time that lecithin administration was begun in the 1982 clinical study by Cohen et al., many patients were taking other medications, including lithium. The patients continued on such medications during the course of the study but no attempt was made to identify particular drugs that might contribute to the observed beneficial effects of lecithin. The possibility that lithium might be essential to the effect was not appreciated. In addition, it was uncertain, both from this paper as well as from the anecdotal reports mentioned above, whether the beneficial effects observed with lecithin were due to choline derived from the digestion of the compound. Lecithin is a major component of cellular membranes and the possibility was recognized that lecithin might be exerting its effects on mania by causing alterations in the membranes of neural cells (Cohen et at., Am. J. Psychiatry 139:1162-1164 (1982)).
The present inventors recently conducted an open, post-hoc reevaluation of the raw data from Cohen's open and double-blind lecithin trials (Cohen et al., Am. J. Psychiatry 139:1162-1164 (1982)). This revealed that it was only those patients who received concurrent lithium with lecithin who showed a substantial and consistent lessening of symptoms associated with mania. Thus, the reevaluation suggested the possibility that lecithin might be exerting its beneficial effect by providing a source of choline which then acts in concert with lithium.
In terms of providing a source of therapeutic choline, lecithin has two main drawbacks. First, lecithin must be broken down into choline by in vivo biochemical processes whose efficiency may vary from individual to individual. Thus, the dosage of choline delivered to different patients by a given concentration of lecithin cannot be accurately predicted. A second problem with the therapeutic use of lecithin stems from its being a phospholipid and the fact that obtaining a beneficial effect on mania has often entailed giving patients very large (15-30 grams) of lecithin per day (see e.g. Cohen et al., Am. J. Psychiatry 137:242-243 (1980); Schreier, Am. J. Psychiatry 139:108-110 (1982)). The intake of such a large quantity of lipid for therapeutic purposes may promote cardiovascular disease or obesity.
The inventors discovered that the concentration of brain choline in humans can be increased by the administration of a salt of choline when the salt is given at a dose of about 50 mg of free choline per kg body weight per day (see Example 1 below; see also, Stoll et al., Biol. Psychiatry 37:170-174 (1995); Stoll et al., Biol. Psychiatry 29:309-321 (1991); Millington et al., NEJM 300:196-197 (1979); Millington et at., Barbeau A (eds) Vol. 5, Raven Press, New York (1979)). This observation, together with the results of the reevaluation of Cohen's lecithin trials and similar considerations, led to the present invention which is directed to methods and compositions for treating patients with bipolar disorder and in which lithium is administered concomitantly with a source of choline other than lecithin. The inventors have demonstrated the effectiveness of this approach on patients with the most severe forms of the illness: rapid cycling and lithium-refractory bipolar disorder.